Pigmentation shows a strong correlation with ultra-violet radiation (UVR) intensity, suggesting that skin color is an adaptive trait in humans. However, there are many genes that affect pigmentation and it is not known how different genes in the pigmentation pathway may have responded to environmental changes in UVR. The goal of the proposed research is to test for the effects of natural selection acting on eleven pigmentation candidate loci in six human populations from different UVR environments. As tests of neutrality are often sensitive to demographic history this study will compare patterns of DNA sequence variation at candidate pigmentation genes with patterns of variation at 90 non-coding loci mapping to genomic regions with moderate to high recombination and low gene density. Thus, patterns of polymorphism at these "neutral" loci are less likely to be affected by selection at linked sites. Summary statistics based on the site frequency spectrum, linkage disequilibrium, population differentiation, and ratios of polymorphism and divergence will be calculated for all loci in three populations from high (Biaka, Mandenka, Papua New Guineans), intermediate (San) and low (French Basque and Han Chinese) UVR environments. New, more powerful tests of neutrality based on empirically determined polymorphism levels at neutral and candidate loci will be developed. A number of hypotheses regarding the role of both purifying and positive directional selection in shaping observed patterns of variation in human pigmentation will be tested. Currently there is a great deal of interest in detecting regions of the genome that have been shaped by selection, as these regions harbor functional variants that may be of biomedical importance. However, like pigmentation, many of these are complex traits under the control of multiple loci. By focusing on a suite of genes that have effects throughout the biochemical, physiological, and developmental pathways associated with a complex phenotypic trait, this study will demonstrate that pigmentation can be used as a model system for understanding the role of selection on loci involved in other complex traits that may have important biomedical functions. [unreadable] [unreadable] [unreadable]